The use of functional neuroimaging techniques (e.g. functional magnetic resonance imaging -- fMRI) in combination with neuropsychological activation paradigms has served to deepen our understanding of regional brain dysfunction in psychiatric disorders, but the application of such types of functional studies to patients with bipolar disorder has been minimal. Bipolar disorder is one of the top ten causes of disability worldwide, yet the neurophysiologic basis of the disorder remains unknown. Few cross-sectional and no longitudinal studies have been done to evaluate the neural and structural correlates of specific mood states. In this proposal, we will use a cross-sectional and longitudinal design to assess brain changes associated with bipolar depression. We will attempt to determine which neural abnormalities are mood state specific (state-related) and which ones exist independent of mood state (trait-related) and may represent an endophenotype of the disorder. We will explore the structural underpinnings of these neural abnormalities. Specifically, we will use novel computational anatomy techniques to develop average anatomic representations for coregistration with fMRI images in bipolar subjects during depression and euthymia and compare them to normal controls. Using such methods, we hope to specifically clarify whether orbitofrontal and amygdala structural deficits are primarily associated with the reduction in neural activity seen in fMRI in bipolar depression and whether these change as a function of mood state. This has not, to our knowledge, been attempted in the bipolar population. This exploration may clarify the neural and structural underpinnings of bipolar disorder, and reveal those that are mood-specific and those that are disease-specific. This clarification may direct the pursuit of targeted neuropharmacologic development and lead to better treatments for patients with bipolar disorder. PUBLIC HEALTH RELEVANCE: The neurophysiologic basis of mood abnormalities in persons with bipolar disorder remains unknown. This application proposes to compare the brain functional deficits in persons with bipolar disorder during depression and in the normal mood state. Understanding the neural correlates associated with the mood changes in bipolar disorder will help us to understand the illness process and aid in the development of improved treatments.